SOX2 promotes the progression of hepatocellular carcinoma by targeting FOXJ3 and activating the PI3K/AKT pathway to regulate autophagy and mitophagy.

OBJECTIVES

Sex-determining region Y-box transcription factor 2 ( SOX2) has been implicated in tumorigenesis across various cancers. This study sought to characterize the expression pattern of SOX2 in hepatocellular carcinoma (HCC) and elucidate its potential mechanism in promoting HCC progression by targeting Forkhead box J3 (FOXJ3) and regulating the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway, autophagy, and mitophagy.

MATERIAL AND

METHODS

SOX2 expression was examined in normal liver epithelial (THLE2) and HCC (Huh7) cells. It was modulated by shRNA-mediated knockdown and plasmid-based overexpression. 5-Ethynyl-2'-deoxyuridine (EdU) fluorescence staining assay, Transwell assays, and flow cytometry were performed to evaluate cell viability and motility. Autophagy and mitophagy were assessed by Western blotting and transmission electron microscopy, and mitochondria-lysosome co-localization was visualized by immunofluorescence staining. The roles of SOX2 and FOXJ3 in the PI3K/AKT signaling pathway were investigated.

RESULTS

SOX2 was markedly upregulated in HCC cells (P <0.001). SOX2 overexpression enhanced the viability and motility of Huh7 cells and inhibited apoptosis, whereas SOX2 knockdown elicited opposite effects (P <0.001). Mechanistically, SOX2 upregulated autophagy-related proteins Microtubule-Associated Protein 1 Light Chain 3 ( LC3)-II/LC3-I and p62, promoted autophagosome formation, increased PTEN-induced kinase 1 ( PINK1) and p-COX4 levels, and facilitated mitochondria-lysosome co-localization (P <0.05). Co-overexpression of FOXJ3 reversed the promotive effects of SOX2 on cell proliferation, migration, autophagy, and mitophagy and attenuated PI3K/AKT pathway activation (P <0.001).

CONCLUSION

SOX2 promotes HCC progression by negatively regulating FOXJ3, thereby activating the PI3K/AKT signaling pathway and inducing autophagy and mitophagy. The potential SOX2-FOXJ3-PI3K/AKT axis may serve as a novel regulatory pathway underlying HCC development and represents a potential target for therapeutic intervention.